JP3685217B2 - Injectable liquid copolymers for soft tissue repair and augmentation - Google Patents
Injectable liquid copolymers for soft tissue repair and augmentation Download PDFInfo
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- JP3685217B2 JP3685217B2 JP29382895A JP29382895A JP3685217B2 JP 3685217 B2 JP3685217 B2 JP 3685217B2 JP 29382895 A JP29382895 A JP 29382895A JP 29382895 A JP29382895 A JP 29382895A JP 3685217 B2 JP3685217 B2 JP 3685217B2
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Description
【0001】
【発明の分野】
本発明は、軟組織の修復および増補で用いるのに適した液状ポリマー類に関する。より具体的には、本発明は、軟組織の修復および増補に適する、生適合性性を示し、生吸収性を示し、注射可能な液状のコポリマー類を提供する。
【0002】
【発明の背景】
顔の欠陥、アクネ、外科手術の瘢痕または老化が原因となる軟組織の欠陥または輪郭の異常の修復または増補は非常に困難であることは認識されている。軟組織の欠陥を矯正する目的で数多くの材料が色々な成功度で用いられたが、現在のところ、如何なる材料も完全には安全および有効でないように思われる。過去において、処方部位に最低限の物理的歪力が存在している小さな軟組織欠陥を矯正する目的で少量の液状シリコンが用いられた。不幸なことには、液状シリコンは該注入部から離れた体部分に移行すると思われ、多様な生理的および臨床的問題を引き起こす。液状シリコンの上記問題および誤用に応答して、FDAは人における液状シリコンの使用を禁止した。
【0003】
1970年代に、再構成した注射可能ウシコラーゲンが利用できるようになり、軟組織の欠陥に有効な治療であると思われた。しかしながら、時間が経つにつれて、このコラーゲン治療の恩恵は短命であることが確認された、即ちこのコラーゲンは2〜3カ月で再吸収される。更に、この材料を使用する場合、該コラーゲン中のウシ蛋白質に対するアレルギー反応を回避するための安全手段を用いなくてはならない。該欠点を解決するため、この治療の効果を約6カ月にまで伸ばす架橋コラーゲンが導入された。しかしながら、アレルギー反応はこの架橋コラーゲン材料を用いても起こり、依然として該架橋材料の頻繁な再投与を行う必要がある。
【0004】
最近、数人の著者が、軟組織の修復または増補で使用可能な新規材料、例えばコラーゲンおよび液状シリコンを用いた時に以前に経験した問題をいくらか回避する、水系ゲル中の生適合性セラミック粒子、熱可塑性材料、熱硬化性材料および乳酸を基とするポリマーブレンド物などを記述した。
【0005】
水系ゲル中の生適合性セラミック粒子の注射可能移植物は米国特許第5,204,382号の中でWallace他によって初めて提案された。該移植物は、粘性のあるポリマー(例えばポリエチレングリコール、ヒアルロン酸、ポリ(メタアクリル酸ヒドロキシエチル)およびコラーゲン)中の水系ゲル担体と混合された、非生物源由来の燐酸カルシウムのセラミック粒子から成っていた。該材料は一般に無毒であるが、非吸収性粒子材料が遠い部位に移行することに関連して、該粒子の使用に関係する危険性が存在すると思われる。
【0006】
熱可塑性および熱硬化性の欠陥充填材は米国特許第4,938,763号、5,278,201号および5,278,202号の中でDunn他によって最初記述された。該特許の中でDunnは、固体状移植物をインサイチューで生じさせる目的で熱可塑性材料を溶媒と一緒に用いることおよび熱可塑性材料を硬化剤と一緒に用いることの両方を提案している。Dunnが熱可塑材として用いる目的で提案した生分解性材料は容認されるものであると思われるが、組織の中に注入する目的でこれらを溶解させるために必要とされる溶媒は到底容認されるものでないと思われる。更に、Dunnの熱可塑性および熱硬化性材料は凝固することから、これらは軟組織の充填で限定された利用度を有する。同様な市販材料は約10,000psiの極限降伏応力を示し、比較として、人の皮膚は500〜2,000psiの極限降伏応力を示す。従って、触感関心により、Dunnが提案した熱可塑性および熱硬化性材料は軟組織の増補または修復、特に皮膚の増補または修復で用いるにはあまりにも堅すぎると思われる。
【0007】
乳酸を基とする非晶質オリゴマーと結晶性オリゴマー類またはポリマー類とのポリマーブレンド物を用いた軟組織修復または増補も提案された(Buchholz他、4,235,312 A1)。Buchholzのブレンド物は、骨ワックスとしての使用で既に記述された乳酸とグリコール酸の脆いコポリマー類の代わりとなる、吸収性移植物として使用可能なペースト状〜ワックス状の材料を提供する目的で開発された。しかしながら、該ブレンド物を注射可能な軟組織欠陥充填材として使用するのは適切でないと思われる、何故ならば、これらは針の中を通して注入するにはあまりにも高い粘性を示し、このことが該ブレンド物の有用性を有意に制限しているからである。更に、Buchholzによって記述された低分子量の液状オリゴマー類は体液内でわずかに溶解性を示し、このことは、該オリゴマー類が移植部位から体の他の部位に迅速に拡散するであろうことを意味する。
【0008】
前に考察した軟組織増補材料の欠陥を鑑み、新規な軟組織増補材料を開発する必要があることは明らかである。新規な増補材料いずれにも、理想的には、前に考察した材料のいずれか1つが有さないいくつかの重要な特性を持たせる。例えば、新規な増補材料はいずれも、組織の長期慢性的刺激または非吸収性材料が体の異なる領域に経時的に移行する可能性を回避するように、完全な吸収性を示すべきである。該新規増補材料は、また、該増補材料の頻繁な再投与を避ける目的で少なくとも6カ月間軟組織増補を与えるべきである。更に、新規な軟組織増補材料は好適には注射による投与が容易であるべきである。最後に、理想的な軟組織増補材料は、実物のような組織の増補を与えるように、該新規材料を移植しようとする組織に適当な度合の順応性を示すものである。上で考察したように、現在利用できる材料はいずれも上記特性を全く有さない。
【0009】
従って、安全で、注射可能であり、長期存続し、生吸収性を示す、軟組織修復および増補材料を提供することが本発明の目的である。
【0010】
【発明の要約】
本発明は、動物において軟組織の修復または増補材料として用いるのに適する注射可能な生吸収性液状コポリマー類を提供し、これは、少なくとも2種の第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマーを含み、ここで、該第一ラクトン繰り返し単位はε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位(これは本発明の目的に対して1,4−ジオキセパン−2−オンおよび1,5−ジオキセパン−2−オンを意味する)およびそれらの組み合わせより成る群から選択され、そして該第二ラクトン繰り返し単位は、グリコリド繰り返し単位、ラクチド繰り返し単位(これを本発明の目的に対してL−ラクチド、D−ラクチドまたはD,L−ラクチド繰り返し単位であると定義する)、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される。
【0011】
本発明の別の態様において、また、注射可能な生吸収性液状コポリマーが中に充填されている前充填(prefilled)薬学容器も提供し、これは、a)少なくとも2種の第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマー[ここで、該第一ラクトン繰り返し単位は、ε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせより成る群から選択され、そして該第二ラクトン繰り返し単位は、グリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される]、およびb)上記液状ポリマー類を貯蔵するための容器[ここで、上記容器は筒状貯蔵領域を有しそして上記筒状貯蔵領域に出口および末端が備わっており、該出口は取り外し可能無菌シールを有し、該末端は、上記筒状貯蔵領域の中に進み得る可動無菌シールを有する]を含む。
【0012】
本発明の更に別の態様において、また、注射可能生吸収性液状ポリマー類を投与するのに適した薬学キットも提供し、これは、a)少なくとも2種の第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマー[ここで、該第一ラクトン繰り返し単位は、ε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせより成る群から選択され、そして該第二ラクトン繰り返し単位は、グリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される]、およびb)上記液状ポリマー類を入れるデバイス[ここで、上記デバイスには、上記液状ポリマー類のための出口、該出口を通して該液状ポリマー類を放出させるための排出器、および該液状ポリマー類を体内の部位に投与するために該出口にはめ込まれる中空管状部材が備わっている]を含む。
【0013】
本発明のさらなる態様において、また、動物内の軟組織を修復または増補する方法も提供し、これは、a)修復または増補すべき動物の軟組織を選択し、そしてb)少なくとも2種の第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマーで構成される軟組織の修復増補材料として用いるのに適する注射可能生吸収性液状ポリマー[ここで、該第一ラクトン繰り返し単位は、ε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせより成る群から選択され、そして該第二ラクトン繰り返し単位は、グリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される]を該動物の軟組織の中に入れることを含む。
【0014】
【発明の詳細な記述】
我々は、驚くべきことに、モノマー類の適当な組み合わせを選択することによって軟組織の修復および増補で用いるに適切な生吸収性液体を生じさせることができることを見い出した。該生吸収性液状ポリマー類は、加熱も溶媒も用いることなくシリンジおよび針を用いて該材料を軟組織の中に注入することを可能にする顕著に低い粘性を有する。更に、該液状ポリマー類は、移植後に硬化する材料とは異なり、自然のままの組織に類似した順応性を有する皮膚組織を回復させるに適切である。
【0015】
該液状ポリマー類は、バルキング剤(bulking agent)が必要とされる動物の体の中の如何なる部分でも、所望の化粧または人工器官効果を与える処置量で投与可能である(例えば皮内、皮下、筋肉内および粘膜下)。該液状ポリマー類は人および家畜、例えば犬、猫、牛、羊、馬および霊長類を含む多様な動物において使用可能である。
【0016】
体温で流体である適切な無毒の生吸収性コポリマー類およびターポリマー類が該注射可能液状ポリマーとして使用可能である。該ポリマー類は、10℃またはそれ以下のガラス転移温度を有する特徴的に非結晶性のポリマー類である。特に、該液状コポリマー類は、約65モル%〜約35モル%の範囲でε−カプロラクトン、トリメチレンカーボネート、エーテルラクトン(これを本発明の目的で1,4−ジオキセパン−2−オンおよび1,5−ジオキセパン−2−オンであると定義する)繰り返し単位またはそれらの組み合わせで構成されていて、該ポリマーの残りは、グリコリド、ラクチド(これはまた本発明の目的でD−ラクチド、L−ラクチドおよびD,L−ラクチドを包含する)、p−ジオキサノンおよびそれらの組み合わせより成る群から選択されるモノマーによって作られる第二ラクトン繰り返し単位である。更に、非結晶性液状コポリマーを与えるようにε−カプロラクトン、トリメチレンカーボネートまたはエーテルラクトンを共重合させてもよい。好適なものは、約65モル%〜約35モル%の範囲でε−カプロラクトンまたはエーテルラクトン繰り返し単位で構成される該コポリマーの残りがトリメチレンカーボネート繰り返し単位である液状コポリマー類である。該液状ポリマー類は、線状、分枝または星状分枝している、統計学的にランダムなコポリマー類、ターポリマー類など、非晶質のブロックコポリマー類、ターポリマー類などであり得る。適切なターポリマー類の例は、ポリ(グリコリド−コ−ε−カプロラクトン−コ−p−ジオキサノン)およびポリ(ラクチド−コ−ε−カプロラクトン−コ−p−ジオキサノン)より成る群から選択されるターポリマー類であり、ここで、ε−カプロラクトン繰り返し単位のモルパーセントは約35〜約65モルパーセントである。好適なものは、40〜60モルパーセントの範囲でε−カプロラクトン繰り返し単位を有するターポリマー類である。また、組織内で炎症反応を引き起こし得る未反応のモノマー類を本質的に除去する目的で該ポリマー類を精製する。
【0017】
最も好適なものは、ポリ(ε−カプロラクトン−コ−トリメチレンカーボネート)、ポリ(ラクチド−コ−トリメチレンカーボネート)、ポリ(ε−カプロラクトン−コ−p−ジオキサノン)、ポリ(トリメチレンカーボネート−コ−p−ジオキサノン)、ポリ(ε−カプロラクトン−コ−ラクチド)、ポリ(ラクチド−コ−1,5−ジオキセパン−2−オン)、ポリ(1,5−ジオキセパン−2−オン−コ−p−ジオキサノン)、ポリ(ラクチド−コ−1,4−ジオキセパン−2−オン)およびポリ(1,4−ジオキセパン−2−オン−コ−p−ジオキサノン)より成る群から選択される液状ポリマー類である。該ポリマー類内のε−カプロラクトン、トリメチレンカーボネートまたはエーテルラクトン繰り返し単位のモルパーセントを、約65〜約35モルパーセントの範囲、好適には40〜60モルパーセントの範囲にすべきである。最も好適には、該液状ポリマー類は統計学的にランダムなコポリマー類である。
【0018】
本発明の液状ポリマー類は、溶媒などの存在なしに室温(25℃)で液体であることによって特徴づけられる。該液状コポリマー類は、25℃のヘキサフルオロイソプロパノール(HFIP)の溶液1dL当たり0.10gで測定した時約0.05dL/g〜約0.5dL/g、好適には約0.05dL/g〜約0.3dL/g、最も好適には0.1dL/g〜0.2dL/gの範囲のインヘレント粘度を示すべきである。0.05dL/g以下のインヘレント粘度を有する液状コポリマーは体液中に僅かに溶解する可能性があり、そして0.5dL/gより高いインヘレント粘度を有する液状コポリマーはあまりにも粘性が高すぎて容易に注入することができないであろう。
【0019】
該ポリマー類は開環重合反応で生じさせ得る。現在のところ、高沸点のアルコール類(例えば1−ドデカノール)、ジオール類およびトリオール類(例えば1,2−プロパンジオール,1,3−プロパンジオール、ジエチレングリコールまたはグリセロール)またはポリオール類(例えばポリエチレングリコール類またはポリプロピレングリコール類)を用いて該開環重合を開始させるのが好適である。更に、上述したモノマー類のいくらかを相当量の相当する酸で置き換えてもよい(例えばグリコリドの代わりに2当量のグリコール酸を用いるか或はL−ラクチドの代わりに2当量のL−乳酸を用いる)。
【0020】
該液状コポリマー類に持たせることが望まれる具体的な特性に応じて、該液状コポリマー類に色々な量で異なるコポリマー類を含有させ得る。
【0021】
該液状コポリマー類の粘度もまた、該液状コポリマー類の分子量に加えて液体として使用される該ポリマー類の組成に応じて変化し得る。一般に、該液状コポリマー類の粘度は、毛細管液体測定法で測定した時、10,000ポイズ未満であり、好適には約20ポイズ〜約2,000ポイズの範囲であろう。
【0022】
該注射可能液状コポリマー類は、多様な軟組織修復および増補操作で使用可能である。例えば、該液状ポリマー類は、これらに限定するものでないが、瘢痕のカモフラージュ、くぼみの充填、不規則さの平滑化、片側顔面萎縮における非対称性、第二鰓弓症候群、顔面脂肪異栄養症の矯正、および年令に関係したしわのカモフラージュに加えて顔面突出部(唇、額など)の増補を含む顔面組織の修復または増補で使用可能である。更に、該注射可能液状ポリマー類は、括約筋機能の回復または改善、例えば緊張性尿失禁の治療で使用可能である。該注射可能液状ポリマー類の他の使用には、また、尿管下注入による膀胱尿管逆流(子供における尿管入り口の不完全機能)の治療および人体における一般目的充填材としての該液状ポリマー類の応用が含まれ得る。
【0023】
注射可能な生分解性液状ポリマー類のための外科用途には、これらに限定するものでないが、顔面輪郭付け(渋面または無毛線、アクネ瘢痕、ほほのくぼみ、垂直または口周囲の唇線、マリオネット線または口の交連、心配または額線、烏の足跡または眼窩周囲の線、深笑い線または鼻唇のひだ、笑い線、顔面瘢痕、唇など);尿道−膀胱接合部から外部括約筋の所またはその回りの尿道に沿った尿道粘膜下組織の中に注入することを含む尿道周囲への注入;尿の逆流を防止するための尿管への注入;組織をかさ高くして逆流を防止するための胃腸管組織への注入;内部または外部括約筋癒合におけるおよび拡張管腔癒合のための補助;硝子体液を置換するためまたは網膜剥離で眼圧を維持するための眼内注入;逆流または感染伝播を防止するために一時的にその出口をふさぐための解剖学的導管への注入;外科手術または萎縮後の咽頭リハビリ;および化粧的または治療的な影響で増補可能な他の如何なる軟組織も含まれる。上記生成物を使用すると思われる外科専門医には、これらに限定するものでないが、形成および再建外科医、皮膚科医、顔面形成外科医、美容外科医、耳鼻咽頭科医、泌尿器科医、婦人科医、胃腸病専門医、眼科医、および上記生成物を利用する資格のある他の如何なる医師も含まれる。
【0024】
更に、本発明の液状コポリマーを用いた投与および患者の治療を容易にする目的で、これと一緒に薬学活性を示す化合物またはアジュバントを投与することができる。本発明の液状ポリマー類と一緒に共投与可能な薬学活性剤には、これらに限定するものでないが、麻酔薬(例えばリドカイン)および抗炎症薬(例えばコルチゾン)が含まれる。
【0025】
シリンジおよび針または種々のデバイスを用いて該液状コポリマー類を投与することができる。本技術分野では粘性のある液体を投与する目的で数種の送出用デバイス、例えば米国特許第4,664,655号および4,758,234号(これらは引用することによって本明細書に組み入れられる)の中でOrentriech博士が記述したカープル(carpule)デバイスが開発および記述された。更に、医者が該液状コポリマーの送出をできるだけ容易に行うことができるようにする目的で、てこ作用を用いた注入ラシェット(rachet)機構または動力を用いた送出機構を用いてもよい。現在のところ、2つの末端を有する筒状容器またはカートリッジの中に該液状ポリマー類を前充填するのが好適である。第一末端を、これがプランジャーを受け入れるように適合させそしてその中に可動シールを位置させる。第二末端または出口を取り外し可能シールで覆いそして針の外被の中にはめ込むように適合させて、該容器内の該液状コポリマーを該出口から出して針の中にか或は該投与デバイスの他の中空管状部材の中に入れることを可能にする。該液状コポリマー類は、また、該液状コポリマー類を入れるデバイスを含むキットの形態で販売可能であると考える。該デバイスに、上記液状コポリマー類のための出口、該液状コポリマー類を放出させるための排出器、および該液状コポリマー類を動物に投与するために該出口にはめ込む中空管状部材を備える。
【0026】
本発明の実施を更に説明する目的で以下の非制限実施例を与える。
【0027】
【実施例】
実施例1
50/50の初期モル組成におけるε−カプロラクトン/L−ラクチドの液状ポリマー類
炎乾燥した250mLの一口丸底フラスコに、ε−カプロラクトンを57.1グラム(0.50モル)、L−ラクチドを72.1グラム(0.50モル)、蒸留したグリセロールを4.00mL(55ミリモル)およびトルエン中0.33Mのカプリル酸第一錫溶液を0.10mL(34μモル)仕込んだ。このフラスコに炎乾燥した機械撹拌機を取り付けた。窒素を用いた排気を行う前に、この反応槽を窒素で3回浄化した。この反応混合物を160℃に加熱しそしてこの温度で約18〜20時間維持した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)110℃で約16時間乾燥させた。このコポリマーは25℃のヘキサフルオロイソプロパノール(HFIP)中で0.14dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。プロトンNMRによりPCL/PLAのモル比は53.7/46.3であることを確認した。
【0028】
実施例2
50/50の初期モル組成におけるε−カプロラクトン/L−ラクチドの液状ポリマー類
グリセロールを4.00mL用いる代わりに1−ドデカノールを13.6mL用いそしてカプリル酸第一錫溶液を0.10mL用いる代わりに0.12mL(40μm)用いる以外は本質的に実施例1の操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)110℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.15dL/gのインヘレント粘度を示した。このコポリマーは室温で粘性のある液体であった。プロトンNMRによりPCL/PLAのモル比は51.5/48.5であることを確認した。
【0029】
実施例3
50/50の初期モル組成におけるε−カプロラクトン/L−ラクチドの液状ポリマー類
1−ドデカノールを13.6mLの代わりに5.6mL用いる以外は本質的に実施例2の操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)110℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.28dL/gのインヘレント粘度を示した。このコポリマーは室温で非常に粘性のある液体であった。プロトンNMRによりPCL/PLAのモル比は50.5/49.5であることを確認した。
【0030】
実施例4
50/50初期モル組成におけるε−カプロラクトン/L−ラクチドの液状ポリマー類
1−ドデカノールを5.6mL用いる代わりにプロピレングリコール(USPグレード)を4.4mL(60ミリモル)用いる以外は本質的に実施例3の操作を繰り返した。このコポリマーは25℃のHFIP中で0.17dL/gのインヘレント粘度を示した。
【0031】
実施例5A
50/50の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
炎乾燥した250mLの一口丸底フラスコに、ε−カプロラクトンを57.1グラム(0.50モル)、p−ジオキサノンを51.0グラム(0.50モル)、蒸留したグリセロールを4.00mL(55ミリモル)およびトルエン中0.33Mのカプリル酸第一錫溶液を0.12mL(40μモル)仕込んだ。このフラスコに炎乾燥した機械撹拌機を取り付けた。窒素を用いた排気を行う前に、このフラスコを窒素で3回浄化した。この反応混合物を140℃に加熱しそしてこの温度で約24時間維持した。次に、この反応混合物を110℃に冷却しそしてこの温度で24時間維持した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約32時間乾燥させた。このコポリマーは25℃のHFIP中で0.14dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。プロトンNMRによりPCL/PDSのモル比は53.2/46.8であることを確認した。
【0032】
実施例5B
50/50の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
炎乾燥した250mLの一口丸底フラスコに、ε−カプロラクトンを57.1グラム(0.50モル)、p−ジオキサノンを51.0グラム(0.50モル)、プロピレングリコール(USP)を3.7mL(50ミリモル)およびトルエン中0.33Mのカプリル酸第一錫溶液を0.12mL(40μモル)仕込んだ。このフラスコに炎乾燥した機械撹拌機を取り付けた。窒素を用いた排気を行う前に、このフラスコを窒素で3回浄化した。この反応混合物を140℃に加熱しそしてこの温度で約24時間維持した後、浴温度を110℃に下げそしてこの温度で24時間維持した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約32時間乾燥させた。このコポリマーは25℃のHFIP中で0.22dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。プロトンNMRによりPCL/PDSのモル比は52.4/47.6であることを確認した。
【0033】
実施例5C
60/40の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
ε−カプロラクトンを68.48グラム(0.60モル)およびp−ジオキサノンを40.83グラム(0.40モル)用いる以外は本質的に実施例5Aの操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約80時間乾燥させた。このコポリマーは25℃のHFIP中で0.19dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。プロトンNMRによりPCL/PDSのモル比は57.2/42.8であることを確認した。
【0034】
実施例5D
40/60の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
ε−カプロラクトンを45.7グラム(0.40モル)およびp−ジオキサノンを61.3グラム(0.60モル)用いる以外は本質的に実施例5Aの操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約80時間乾燥させた。このコポリマーは25℃のHFIP中で0.18dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。プロトンNMRによりPCL/PDSのモル比は46.7/53.3であることを確認した。
【0035】
実施例6
50/50の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
グリセロールを4.00mL用いる代わりに1−ドデカノールを13.6mL用いる以外は本質的に実施例5Aの操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約32時間乾燥させた。このコポリマーは25℃のHFIP中で0.16dL/gのインヘレント粘度を示した。このコポリマーは室温で液体であった。
【0036】
実施例7
50/50の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
1−ドデカノールを13.6mLの代わりに6.8mL用いる以外は本質的に実施例5Aの操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.24dL/gのインヘレント粘度を示した。このコポリマーは室温で粘性のある液体であった。プロトンNMRによりPCL/PDSのモル比は53.6/46.4であることを確認した。
【0037】
実施例8
50/50の初期モル組成におけるε−カプロラクトン/p−ジオキサノンの液状ポリマー類
1−ドデカノールを6.8mL用いる代わりにプロピレングリコール(USP)を4.4mL(60ミリモル)用いる以外は本質的に実施例7の操作を繰り返した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.17dL/gのインヘレント粘度を示した。このコポリマーは室温で粘性のある液体であった。
【0038】
実施例9
50/50の初期モル組成におけるε−カプロラクトン/トリメチレンカーボネートの液状ポリマー類
炎乾燥した250mLの一口丸底フラスコに、ε−カプロラクトンを57.1グラム(0.50モル)、トリメチレンカーボネートを51.0グラム(0.50モル)、プロピレングリコール(USP)を4.4mL(60ミリモル)およびトルエン中0.33Mのカプリル酸第一錫溶液を0.10mL(34μモル)仕込んだ。このフラスコに炎乾燥した機械撹拌機を取り付けた。窒素を用いた排気を行う前に、このフラスコを窒素で3回浄化した。この反応混合物を160℃に加熱しそしてこの温度で約18〜20時間維持した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.20dL/gのインヘレント粘度を示した。このコポリマーは室温で粘性のある液体であった。
【0039】
実施例10
90/10の初期モル組成におけるε−カプロラクトン/トリメチレンカーボネートの液状ポリマー類
炎乾燥した250mLの一口丸底フラスコに、ε−カプロラクトンを102.7グラム(0.90モル)、トリメチレンカーボネートを10.2グラム(0.10モル)、プロピレングリコール(USP)を2.9mL(40ミリモル)およびトルエン中0.33Mのカプリル酸第一錫溶液を0.10mL(34μモル)仕込んだ。このフラスコに炎乾燥した機械撹拌機を取り付けた。窒素を用いた排気を行う前に、このフラスコを窒素で3回浄化した。この反応混合物を160℃に加熱しそしてこの温度で約18〜20時間維持した。如何なる未反応モノマーも除去する目的でこのコポリマーを真空下(0.1mmHg)80℃で約16時間乾燥させた。このコポリマーは25℃のHFIP中で0.25dL/gのインヘレント粘度を示した。このコポリマーは室温で粘性のある液体であった。
【0040】
実施例11
液状の吸収性コポリマー類の粘度
この実施例では、実施例1〜9で記述したのと同様な様式で調製した液状の吸収性ポリマー類に関する粘度データを与える。
【0041】
毛細管流体測定法により該ポリマー類の粘度を測定した。該液状の吸収性ポリマー類に関する粘度データを表1、2および3に与える。
【0042】
【表1】
【0043】
【表2】
【0044】
【表3】
【0045】
参考例1
ポリ(L−乳酸)オリゴマー類
ドイツ特許出願公開第DE 4,235,312 A1号の実施例1に記述されているのと同様にしてポリ(L−乳酸)オリゴマー類を調製した。例えば、機械撹拌機、蒸留ヘッドおよびストッパーが備わっている奇麗な250mLの3つ口丸底フラスコに85重量%のL−乳酸溶液を100.0グラム(0.94モル)移した。アスピレーターを用いてこの反応容器の排気(約25mmHg)を行った後、オイルバスを用いて150℃に5時間加熱した。22mL(1.2モル)の水を集めた。この熱ポリ(L−乳酸)オリゴマー(A)を広口ジャーの中に注ぎ込み、そして窒素ガス雰囲気下で室温に冷却した。このオリゴマー(A)は、25℃のHFIP中で0.06dL/gのインヘレント粘度を示す高粘性液体であった。このオリゴマー(A)の溶融粘度をRheometries RDA II粘度計で測定し、そして25℃で18,000ポイズであり、実際ニュートン的(Newtonian)であることを確認した。
【0046】
反応時間を長くして24時間にする以外は上記操作を繰り返した。25mLの水を集めた。その結果として得られるオリゴマー(B)は、Fisher−Johns融点測定装置で測定した時の融点範囲が75℃〜83℃である結晶性固体であった。このオリゴマー(B)のインヘレント粘度は、25℃のHFIP中で0.15dL/gであった。
【0047】
タイゴン(tygon)配管を通して乾燥窒素ガス流れおよびファイヤーストーン(Firestone)バルブに連結させた口を有するアダプタおよび機械撹拌機が備わっている250mLの丸底フラスコに各オリゴマーを20.0グラム移すことによって、オリゴマー(A)とオリゴマー(B)の50:50(重量/重量)ブレンド物を製造した。この混合物を160℃に30分間加熱し、広口ジャーに移し、そして不活性雰囲気下で室温に冷却した。このブレンド物は、25℃のHFIP中で0.08dL/gのインヘレント粘度を示す透明な堅い材料であった。このブレンド物は、実際、管の中を一晩かかってゆっくりと流れることで示されるように、室温で非常に粘性のある液体であった。室温でジャーの中に5週間放置した後でもまだこのブレンド物の大部分は透明であり、その表面層のみが半透明であった。
【0048】
本発明の特徴および態様は以下のとうりである。
【0049】
1. 注射可能な生吸収性液状コポリマーが中に充填されている前充填薬学容器であって、
複数の少なくとも2種の異なる第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマーであって、該第一ラクトン繰り返し単位がε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせから成る群から選択されそして該第二ラクトン繰り返し単位がグリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される液状ポリマー、および
上記液状ポリマーを貯蔵するための容器であって、上記容器が筒状貯蔵領域を有しそして上記筒状貯蔵領域に出口および末端が備わっており、該出口が取り外し可能無菌シールを有し、該末端が、上記筒状貯蔵領域の中に進み得る可動無菌シールを有する容器、
を含む前充填薬学容器。
【0050】
2. 該液状コポリマーが、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位でその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がエーテルラクトン繰り返し単位でその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がトリメチレンカーボネート繰り返し単位でありその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位であり該ポリマーの残りがトリメチレンカーボネート繰り返し単位であるポリマー類、および約65モル%〜約35モル%がエーテルラクトン繰り返し単位でありその残りがトリメチレンカーボネート繰り返し単位であるポリマー類より成る群から選択され約0.05dL/g〜約0.5dL/gのインヘレント粘度を示す非結晶性液状コポリマーである第1項の前充填薬学容器。
【0051】
3. 該液状コポリマーがポリ(ε−カプロラクトン−コ−トリメチレンカーボネート)、ポリ(ラクチド−コ−トリメチレンカーボネート)、ポリ(ε−カプロラクトン−コ−p−ジオキサノン)、ポリ(トリメチレンカーボネート−コ−p−ジオキサノン)、ポリ(ε−カプロラクトン−コ−ラクチド)、ポリ(ラクチド−コ−1,4−ジオキセパン−2−オン)、ポリ(1,4−ジオキセパン−2−オン−コ−p−ジオキサノン)、ポリ(ラクチド−コ−1,5−ジオキセパン−2−オン)およびポリ(1,5−ジオキセパン−2−オン−コ−p−ジオキサノン)より成る群から選択される第1項の前充填薬学容器。
【0052】
4. 軟組織の修復または増補材料として用いるに適切な注射可能生吸収性液状コポリマーを投与するに適切な薬学キットであって、
複数の少なくとも2種の異なる第一ラクトン繰り返し単位の液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状コポリマーであって、該第一ラクトン繰り返し単位がε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせより成る群から選択されそして該第二ラクトン繰り返し単位がグリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される液状コポリマー、および
上記液状ポリマー類を入れるデバイスであって、上記デバイスに上記液状ポリマー類のための出口、該出口を通して該液状ポリマー類を放出させるための排出器、および該液状ポリマー類を体内の部位に投与するために該出口にはめ込まれる中空管状部材が備わっているデバイス、
を含む薬学キット。
【0053】
5. 該液状コポリマーが、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位でその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がエーテルラクトン繰り返し単位でありその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がトリメチレンカーボネート繰り返し単位でその残りが該第二ラクトン繰り返し単位であるポリマー類、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位であり該ポリマーの残りがトリメチレンカーボネート繰り返し単位であるポリマー類、および約65モル%〜約35モル%がエーテルラクトン繰り返し単位でありその残りがトリメチレンカーボネート繰り返し単位であるポリマー類より成る群から選択される第4項の薬学キット。
【0054】
6. 該液状コポリマーがポリ(ε−カプロラクトン−コ−トリメチレンカーボネート)、ポリ(ラクチド−コ−トリメチレンカーボネート)、ポリ(ε−カプロラクトン−コ−p−ジオキサノン)、ポリ(トリメチレンカーボネート−コ−p−ジオキサノン)、ポリ(ε−カプロラクトン−コ−ラクチド)、ポリ(ラクチド−コ−1,4−ジオキセパン−2−オン)、ポリ(1,4−ジオキセパン−2−オン−コ−p−ジオキサノン)、ポリ(ラクチド−コ−1,5−ジオキセパン−2−オン)およびポリ(1,5−ジオキセパン−2−オン−コ−p−ジオキサノン)より成る群から選択される第4項の薬学キット。
【0055】
7. 動物における軟組織を修復または増補する方法であって、
修復または増補すべき動物の軟組織を選択し、
複数の少なくとも2種の異なる第一ラクトン繰り返し単位で構成される液状ポリマー類および複数の第一ラクトンおよび第二ラクトン繰り返し単位の液状ポリマー類より成る群から選択される液状ポリマーで構成される軟組織の修復または増補材料として用いるのに適した注射可能生吸収性液状コポリマーであって、該第一ラクトン繰り返し単位がε−カプロラクトン繰り返し単位、トリメチレンカーボネート繰り返し単位、エーテルラクトン繰り返し単位およびそれらの組み合わせより成る群から選択されそして該第二ラクトン繰り返し単位がグリコリド繰り返し単位、ラクチド繰り返し単位、p−ジオキサノン繰り返し単位およびそれらの組み合わせより成る群から選択される注射可能生吸収性液状コポリマーを該動物の軟組織の中に入れる、
段階を含む方法。
【0056】
8. 該液状コポリマーが、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位でその残りが該第二ラクトン群の繰り返し単位であるポリマー類、約65モル%〜約35モル%がエーテルラクトン繰り返し単位でありその残りが第二ラクトン群の繰り返し単位であるポリマー類、約65モル%〜約35モル%がトリメチレンカーボネート繰り返し単位でありその残りが第二ラクトン群の繰り返し単位であるポリマー類、約65モル%〜約35モル%がε−カプロラクトン繰り返し単位であり該ポリマーの残りがトリメチレンカーボネート繰り返し単位であるポリマー類、および約65モル%〜約35モル%がエーテルラクトン繰り返し単位でその残りがトリメチレンカーボネート繰り返し単位であるポリマー類より成る群から選択される第7項の方法。
【0057】
9. 該液状ポリマーがポリ(ε−カプロラクトン−コ−トリメチレンカーボネート)、ポリ(ラクチド−コ−トリメチレンカーボネート)、ポリ(ε−カプロラクトン−コ−p−ジオキサノン)、ポリ(トリメチレンカーボネート−コ−p−ジオキサノン)、ポリ(ε−カプロラクトン−コ−ラクチド)、ポリ(ラクチド−コ−1,4−ジオキセパン−2−オン)、ポリ(1,4−ジオキセパン−2−オン−コ−p−ジオキサノン)、ポリ(ラクチド−コ−1,5−ジオキセパン−2−オン)およびポリ(1,5−ジオキセパン−2−オン−コ−p−ジオキサノン)より成る群から選択される第8項の方法。
【0058】
10. 選択する該動物の軟組織が皮膚である第8項の方法。
【0059】
11. 該液状ポリマーを顔の軟組織に注入して顔の輪郭を与える第8項の方法。
【0060】
12. 選択する該動物の軟組織が括約筋である第8項の方法。
【0061】
13. 選択する該動物の軟組織が尿膀胱である第8項の方法。[0001]
FIELD OF THE INVENTION
The present invention relates to liquid polymers suitable for use in soft tissue repair and augmentation. More specifically, the present invention provides biocompatible, bioabsorbable, injectable liquid copolymers that are suitable for soft tissue repair and augmentation.
[0002]
BACKGROUND OF THE INVENTION
It has been recognized that repair or augmentation of soft tissue defects or contour abnormalities due to facial defects, acne, surgical scars or aging is very difficult. A number of materials have been used with varying degrees of success to correct soft tissue defects, but at present, no material appears to be completely safe and effective. In the past, small amounts of liquid silicon have been used to correct small soft tissue defects that have minimal physical strain at the prescription site. Unfortunately, liquid silicon appears to migrate to body parts away from the injection site, causing a variety of physiological and clinical problems. In response to the above problems and misuse of liquid silicon, the FDA has banned humans from using liquid silicon.
[0003]
In the 1970s, reconstituted injectable bovine collagen became available and appeared to be an effective treatment for soft tissue defects. However, over time, the benefits of this collagen treatment have been confirmed to be short-lived, i.e. the collagen is resorbed in 2-3 months. In addition, when using this material, safety measures must be used to avoid allergic reactions to bovine proteins in the collagen. In order to overcome this drawback, cross-linked collagen was introduced that extends the effectiveness of this treatment to about 6 months. However, allergic reactions also occur with this cross-linked collagen material and still require frequent re-administration of the cross-linked material.
[0004]
Recently, several authors have reported that biocompatible ceramic particles in water-based gels, heat, which avoid some of the problems previously experienced when using new materials such as collagen and liquid silicone that can be used in soft tissue repair or augmentation. We have described plastic materials, thermosetting materials, polymer blends based on lactic acid, and the like.
[0005]
An injectable implant of biocompatible ceramic particles in an aqueous gel was first proposed by Wallace et al. In US Pat. No. 5,204,382. The implant consists of ceramic particles of calcium phosphate derived from a non-biological source mixed with an aqueous gel carrier in viscous polymers such as polyethylene glycol, hyaluronic acid, poly (hydroxyethyl methacrylate) and collagen. It was. Although the material is generally non-toxic, there appears to be a risk associated with the use of the particles in connection with the migration of non-absorbable particulate material to remote sites.
[0006]
Thermoplastic and thermoset defect fillers were first described by Dunn et al. In US Pat. Nos. 4,938,763, 5,278,201 and 5,278,202. In that patent Dunn proposes both the use of a thermoplastic material with a solvent and the use of a thermoplastic material with a hardener for the purpose of generating a solid implant in situ. The biodegradable materials proposed by Dunn for use as thermoplastics appear to be acceptable, but the solvents required to dissolve them for injection into the tissue are well tolerated. It seems not to be. Furthermore, since Dunn's thermoplastic and thermoset materials solidify, they have limited utility in soft tissue filling. Similar commercially available materials exhibit an ultimate yield stress of about 10,000 psi, and as a comparison, human skin exhibits an ultimate yield stress of 500-2,000 psi. Thus, due to tactile concerns, the thermoplastic and thermoset materials proposed by Dunn appear to be too stiff for use in soft tissue augmentation or repair, particularly skin augmentation or repair.
[0007]
Soft tissue repair or augmentation using polymer blends of lactic acid based amorphous oligomers and crystalline oligomers or polymers has also been proposed (Buchholz et al., 4,235,312 A1). Buchholz blends have been developed to provide paste-to-wax-like materials that can be used as absorbent implants to replace the brittle copolymers of lactic acid and glycolic acid already described for use as bone wax. It was done. However, it seems that it is not appropriate to use the blends as injectable soft tissue defect fillers because they exhibit too high a viscosity to be injected through a needle, which This is because the usefulness of the product is significantly limited. In addition, the low molecular weight liquid oligomers described by Buchholz are slightly soluble in body fluids, indicating that the oligomers will diffuse rapidly from the implantation site to other parts of the body. means.
[0008]
Obviously, there is a need to develop new soft tissue augmentation materials in view of the previously discussed defects in soft tissue augmentation materials. Any new augmented material ideally has some important properties that any one of the previously discussed materials does not have. For example, any new augmentation material should exhibit full absorbency so as to avoid the possibility of long-term chronic irritation of tissue or non-absorbable material moving over time to different areas of the body. The new augmentation material should also provide soft tissue augmentation for at least 6 months in order to avoid frequent re-administration of the augmentation material. Furthermore, the new soft tissue augmentation material should preferably be easy to administer by injection. Finally, an ideal soft tissue augmentation material is one that exhibits a suitable degree of conformity to the tissue to which the new material is to be implanted so as to provide real tissue augmentation. As discussed above, none of the currently available materials have any of the above properties.
[0009]
Accordingly, it is an object of the present invention to provide a soft tissue repair and augmentation material that is safe, injectable, lasts long and exhibits bioabsorbability.
[0010]
SUMMARY OF THE INVENTION
The present invention provides injectable bioabsorbable liquid copolymers suitable for use as soft tissue repair or augmentation materials in animals, comprising liquid polymers of at least two first lactone repeat units and a plurality of second polymers. A liquid polymer selected from the group consisting of a liquid polymer of one lactone and a second lactone repeating unit, wherein the first lactone repeating unit is an ε-caprolactone repeating unit, a trimethylene carbonate repeating unit, an ether lactone repeating unit (Which means 1,4-dioxepan-2-one and 1,5-dioxepan-2-one for the purposes of the present invention) and combinations thereof and the second lactone repeat The unit is glycolide repeating unit, lactide repeating unit (this L- lactide for the purposes of the present invention, D- lactide or D, is defined as a L- lactide repeating units), it is selected from p- dioxanone repeating units and the group consisting of combinations thereof.
[0011]
In another aspect of the present invention, there is also provided a prefilled pharmaceutical container filled with an injectable bioabsorbable liquid copolymer, which comprises a) at least two first lactone repeat units. And a liquid polymer selected from the group consisting of a plurality of first lactone and second lactone repeating unit liquid polymers [wherein the first lactone repeating unit is an ε-caprolactone repeating unit, trimethylene carbonate Selected from the group consisting of repeating units, ether lactone repeating units and combinations thereof, and the second lactone repeating unit is selected from the group consisting of glycolide repeating units, lactide repeating units, p-dioxanone repeating units and combinations thereof. And b) the above liquid polymers A container for storage, wherein said container has a cylindrical storage area and said cylindrical storage area is provided with an outlet and a terminal, said outlet having a removable sterile seal, said terminal being Having a movable aseptic seal that can be advanced into a cylindrical storage area.
[0012]
In yet another aspect of the present invention, there is also provided a pharmaceutical kit suitable for administering injectable bioabsorbable liquid polymers, comprising a) liquid polymers of at least two first lactone repeat units. And a liquid polymer selected from the group consisting of a plurality of liquid polymers of a first lactone and a second lactone repeating unit [wherein the first lactone repeating unit is an ε-caprolactone repeating unit, a trimethylene carbonate repeating unit, an ether Selected from the group consisting of lactone repeat units and combinations thereof, and the second lactone repeat unit is selected from the group consisting of glycolide repeat units, lactide repeat units, p-dioxanone repeat units and combinations thereof], and b) A desiccant containing the above liquid polymers. [Wherein the device includes an outlet for the liquid polymers, an ejector for discharging the liquid polymers through the outlet, and the outlet for administering the liquid polymers to a site in the body. A hollow tubular member to be fitted.
[0013]
In a further embodiment of the present invention, there is also provided a method for repairing or augmenting soft tissue in an animal, comprising a) selecting the animal's soft tissue to be repaired or augmented, and b) at least two first lactones. Injectable bioabsorbability suitable for use as a soft tissue repair augmentation material composed of a liquid polymer of repeating units and a liquid polymer selected from the group consisting of liquid polymers of a plurality of first lactone and second lactone repeating units A liquid polymer wherein the first lactone repeat unit is selected from the group consisting of ε-caprolactone repeat units, trimethylene carbonate repeat units, ether lactone repeat units and combinations thereof, and the second lactone repeat unit is Glycolide repeat unit, lactide repeat unit, p-di It involves placing cyclohexanone repeating selected from the group consisting of units and combinations thereof] in the soft tissue of the animal.
[0014]
Detailed Description of the Invention
We have surprisingly found that by selecting an appropriate combination of monomers, a bioabsorbable liquid suitable for use in soft tissue repair and augmentation can be produced. The bioabsorbable liquid polymers have a significantly lower viscosity that allows the material to be injected into soft tissue using a syringe and needle without the use of heat or solvent. In addition, the liquid polymers are suitable for restoring skin tissue that has an adaptability similar to natural tissue, unlike materials that harden after implantation.
[0015]
The liquid polymers can be administered in any part of the animal's body where a bulking agent is needed in a therapeutic amount that provides the desired cosmetic or prosthetic effect (eg, intradermal, subcutaneous, Intramuscular and submucosal). The liquid polymers can be used in a variety of animals including humans and livestock, such as dogs, cats, cows, sheep, horses and primates.
[0016]
Suitable non-toxic bioabsorbable copolymers and terpolymers that are fluid at body temperature can be used as the injectable liquid polymer. The polymers are characteristically amorphous polymers having a glass transition temperature of 10 ° C. or lower. In particular, the liquid copolymers include ε-caprolactone, trimethylene carbonate, ether lactone (for the purposes of the present invention, 1,4-dioxepan-2-one and 1,5 mol% to about 35 mol%). 5-dioxepane-2-one), or a combination thereof, the remainder of the polymer being glycolide, lactide (which is also D-lactide, L-lactide for purposes of the present invention). And D, L-lactide), a second lactone repeat unit made by a monomer selected from the group consisting of p-dioxanone and combinations thereof. Further, ε-caprolactone, trimethylene carbonate or ether lactone may be copolymerized to give an amorphous liquid copolymer. Preferred are liquid copolymers in which the remainder of the copolymer composed of ε-caprolactone or ether lactone repeat units in the range of about 65 mole percent to about 35 mole percent is trimethylene carbonate repeat units. The liquid polymers can be linear, branched or star-branched, statistically random copolymers, terpolymers, etc., amorphous block copolymers, terpolymers, and the like. Examples of suitable terpolymers are terpolymers selected from the group consisting of poly (glycolide-co-ε-caprolactone-co-p-dioxanone) and poly (lactide-co-ε-caprolactone-co-p-dioxanone). Polymers, wherein the mole percent of ε-caprolactone repeat units is from about 35 to about 65 mole percent. Preferred are terpolymers having ε-caprolactone repeat units in the range of 40 to 60 mole percent. The polymers are also purified for the purpose of essentially removing unreacted monomers that can cause an inflammatory response in the tissue.
[0017]
Most preferred are poly (ε-caprolactone-co-trimethylene carbonate), poly (lactide-co-trimethylene carbonate), poly (ε-caprolactone-co-p-dioxanone), poly (trimethylene carbonate-co -P-dioxanone), poly (ε-caprolactone-co-lactide), poly (lactide-co-1,5-dioxepan-2-one), poly (1,5-dioxepan-2-one-co-p- Dioxanone), poly (lactide-co-1,4-dioxepan-2-one) and liquid polymers selected from the group consisting of poly (1,4-dioxepan-2-one-co-p-dioxanone) . The mole percent of ε-caprolactone, trimethylene carbonate or ether lactone repeat units in the polymers should be in the range of about 65 to about 35 mole percent, preferably in the range of 40 to 60 mole percent. Most preferably, the liquid polymers are statistically random copolymers.
[0018]
The liquid polymers of the present invention are characterized by being liquid at room temperature (25 ° C.) without the presence of a solvent or the like. The liquid copolymers are from about 0.05 dL / g to about 0.5 dL / g, preferably from about 0.05 dL / g, measured at 0.10 g / dL of a solution of hexafluoroisopropanol (HFIP) at 25 ° C. It should exhibit an inherent viscosity of about 0.3 dL / g, most preferably in the range of 0.1 dL / g to 0.2 dL / g. Liquid copolymers having an inherent viscosity of 0.05 dL / g or less may be slightly soluble in body fluids, and liquid copolymers having an inherent viscosity greater than 0.5 dL / g are too viscous to be easily Would not be able to be injected.
[0019]
The polymers can be formed by a ring-opening polymerization reaction. Currently, high boiling alcohols (eg 1-dodecanol), diols and triols (eg 1,2-propanediol, 1,3-propanediol, diethylene glycol or glycerol) or polyols (eg polyethylene glycols or It is preferred to initiate the ring-opening polymerization using polypropylene glycols). In addition, some of the monomers described above may be replaced with a substantial amount of the corresponding acid (eg, using 2 equivalents of glycolic acid instead of glycolide or 2 equivalents of L-lactic acid instead of L-lactide). ).
[0020]
Depending on the specific properties desired to be imparted to the liquid copolymers, the liquid copolymers can contain different amounts of different copolymers.
[0021]
The viscosity of the liquid copolymers can also vary depending on the composition of the polymers used as a liquid in addition to the molecular weight of the liquid copolymers. Generally, the viscosity of the liquid copolymers will be less than 10,000 poise, preferably in the range of about 20 poise to about 2,000 poise, as measured by capillary liquid measurement.
[0022]
The injectable liquid copolymers can be used in a variety of soft tissue repair and augmentation operations. For example, the liquid polymers may include, but are not limited to It can be used in correction and repair or augmentation of facial tissues including augmentation of facial protrusions (lips, forehead, etc.) in addition to age-related wrinkle camouflage. Furthermore, the injectable liquid polymers can be used in the recovery or improvement of sphincter function, for example in the treatment of stress urinary incontinence. Other uses of the injectable liquid polymers include treatment of vesicoureteral reflux (imperfect function of the ureteral entrance in children) by subureteral injection and the liquid polymers as general purpose fillers in the human body. Applications of can be included.
[0023]
Surgical applications for injectable biodegradable liquid polymers include, but are not limited to, facial contouring (bacterial or hairless lines, acne scars, cheek depressions, vertical or perioral lip lines, mario Net line or mouth commissure, anxiety or forehead line, eyelid footprint or periorbital line, deep laugh line or nasal lip, laugh line, facial scar, lips, etc.); Or injection around the urethra, including injection into the urethral submucosa along the urethra around it; injection into the ureter to prevent urine reflux; bulk tissue to prevent reflux Injection into the gastrointestinal tract tissue for; assist in internal or external sphincter fusion and for expansion lumen fusion; intraocular injection to replace vitreous fluid or maintain intraocular pressure with retinal detachment; reflux or transmission of infection Prevent Temporarily injection into anatomical conduit for closing the outlet for; surgery or pharynx rehabilitation after atrophy; and cosmetic or therapeutic augmented possible any other soft tissue in the affected also included. Surgeons who are likely to use the above products include, but are not limited to, plastic and reconstructive surgeons, dermatologists, facial plastic surgeons, cosmetic surgeons, otolaryngologists, urologists, gynecologists, Included are gastroenterologists, ophthalmologists, and any other physician qualified to utilize the product.
[0024]
Further, for the purpose of facilitating administration using the liquid copolymer of the present invention and treatment of a patient, a compound or an adjuvant exhibiting pharmacological activity can be administered together therewith. Pharmaceutically active agents that can be co-administered with the liquid polymers of the present invention include, but are not limited to, anesthetics (eg, lidocaine) and anti-inflammatory agents (eg, cortisone).
[0025]
The liquid copolymers can be administered using syringes and needles or various devices. In the art, several delivery devices, such as US Pat. Nos. 4,664,655 and 4,758,234, which are incorporated herein by reference, for the purpose of administering viscous liquids. ) Developed and described the carpule device described by Dr. Orientrich. Furthermore, an injection ratchet mechanism using a lever action or a power delivery mechanism may be used for the purpose of enabling a doctor to deliver the liquid copolymer as easily as possible. Currently, it is preferred to pre-fill the liquid polymers into a cylindrical container or cartridge having two ends. The first end is adapted to receive the plunger and the movable seal is positioned therein. The second end or outlet is covered with a removable seal and adapted to fit into the needle jacket so that the liquid copolymer in the container exits the outlet and into the needle or of the dosing device. It can be placed in other hollow tubular members. It is contemplated that the liquid copolymers can also be sold in the form of a kit that includes a device containing the liquid copolymers. The device comprises an outlet for the liquid copolymers, a discharger for discharging the liquid copolymers, and a hollow tubular member that fits into the outlet for administering the liquid copolymers to an animal.
[0026]
The following non-limiting examples are given for the purpose of further illustrating the practice of the present invention.
[0027]
【Example】
Example 1
Liquid polymers of ε-caprolactone / L-lactide in an initial molar composition of 50/50
In a flame-dried 250 mL single-necked round bottom flask, 57.1 grams (0.50 mole) of ε-caprolactone, 72.1 grams (0.50 mole) of L-lactide, and 4.00 mL (55 Millimoles) and 0.10 mL (34 μmol) of a 0.33 M stannous caprylate solution in toluene. A flame-dried mechanical stirrer was attached to the flask. The reactor was purged with nitrogen three times before venting with nitrogen. The reaction mixture was heated to 160 ° C. and maintained at this temperature for about 18-20 hours. The copolymer was dried under vacuum (0.1 mm Hg) at 110 ° C. for about 16 hours in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.14 dL / g in hexafluoroisopropanol (HFIP) at 25 ° C. This copolymer was liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PLA was 53.7 / 46.3.
[0028]
Example 2
Liquid polymers of ε-caprolactone / L-lactide in an initial molar composition of 50/50
The procedure of Example 1 was essentially repeated except that 13.6 mL of 1-dodecanol was used instead of 4.00 mL of glycerol and 0.12 mL (40 μm) of stannous caprylate solution was used instead of 0.10 mL. . The copolymer was dried under vacuum (0.1 mm Hg) at 110 ° C. for about 16 hours in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.15 dL / g in HFIP at 25 ° C. This copolymer was a viscous liquid at room temperature. Proton NMR confirmed that the PCL / PLA molar ratio was 51.5 / 48.5.
[0029]
Example 3
Liquid polymers of ε-caprolactone / L-lactide in an initial molar composition of 50/50
The procedure of Example 2 was essentially repeated except that 5.6 mL of 1-dodecanol was used instead of 13.6 mL. The copolymer was dried under vacuum (0.1 mm Hg) at 110 ° C. for about 16 hours in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.28 dL / g in HFIP at 25 ° C. This copolymer was a very viscous liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PLA was 50.5 / 49.5.
[0030]
Example 4
Liquid polymers of ε-caprolactone / L-lactide in 50/50 initial molar composition
The procedure of Example 3 was essentially repeated, except that 4.4 mL (60 mmol) of propylene glycol (USP grade) was used instead of 5.6 mL of 1-dodecanol. The copolymer exhibited an inherent viscosity of 0.17 dL / g in HFIP at 25 ° C.
[0031]
Example 5A
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 50/50
In a flame-dried 250 mL single-necked round bottom flask, 57.1 grams (0.50 mole) of ε-caprolactone, 51.0 grams (0.50 mole) of p-dioxanone, and 4.00 mL (55 Millimoles) and 0.12 mL (40 μmol) of 0.33 M stannous caprylate solution in toluene. A flame-dried mechanical stirrer was attached to the flask. The flask was purged with nitrogen three times before evacuating with nitrogen. The reaction mixture was heated to 140 ° C. and maintained at this temperature for about 24 hours. The reaction mixture was then cooled to 110 ° C. and maintained at this temperature for 24 hours. The copolymer was dried for about 32 hours at 80 ° C. under vacuum (0.1 mm Hg) in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.14 dL / g in HFIP at 25 ° C. This copolymer was liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PDS was 53.2 / 46.8.
[0032]
Example 5B
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 50/50
In a flame-dried 250 mL single-necked round bottom flask, 57.1 g (0.50 mol) of ε-caprolactone, 51.0 g (0.50 mol) of p-dioxanone, and 3.7 mL of propylene glycol (USP) (50 mmol) and 0.12 mL (40 μmol) of 0.33 M stannous caprylate solution in toluene was charged. A flame-dried mechanical stirrer was attached to the flask. The flask was purged with nitrogen three times before evacuating with nitrogen. After the reaction mixture was heated to 140 ° C. and maintained at this temperature for about 24 hours, the bath temperature was lowered to 110 ° C. and maintained at this temperature for 24 hours. The copolymer was dried for about 32 hours at 80 ° C. under vacuum (0.1 mm Hg) in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.22 dL / g in HFIP at 25 ° C. This copolymer was liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PDS was 52.4 / 47.6.
[0033]
Example 5C
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 60/40
The procedure of Example 5A was essentially repeated except that 68.48 grams (0.60 mole) of ε-caprolactone and 40.83 grams (0.40 mole) of p-dioxanone were used. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 80 hours in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.19 dL / g in HFIP at 25 ° C. This copolymer was liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PDS was 57.2 / 42.8.
[0034]
Example 5D
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 40/60
The procedure of Example 5A was essentially repeated except that 45.7 grams (0.40 mole) of ε-caprolactone and 61.3 grams (0.60 mole) of p-dioxanone were used. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 80 hours in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.18 dL / g in HFIP at 25 ° C. This copolymer was liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PDS was 46.7 / 53.3.
[0035]
Example 6
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 50/50
The procedure of Example 5A was essentially repeated except that 13.6 mL of 1-dodecanol was used instead of 4.00 mL of glycerol. The copolymer was dried for about 32 hours at 80 ° C. under vacuum (0.1 mm Hg) in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.16 dL / g in HFIP at 25 ° C. This copolymer was liquid at room temperature.
[0036]
Example 7
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 50/50
The procedure of Example 5A was essentially repeated except that 6.8 mL of 1-dodecanol was used instead of 13.6 mL. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 16 hours in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.24 dL / g in HFIP at 25 ° C. This copolymer was a viscous liquid at room temperature. It was confirmed by proton NMR that the molar ratio of PCL / PDS was 53.6 / 46.4.
[0037]
Example 8
Liquid polymers of ε-caprolactone / p-dioxanone in an initial molar composition of 50/50
The procedure of Example 7 was essentially repeated except that 4.4 mL (60 mmol) of propylene glycol (USP) was used instead of 6.8 mL of 1-dodecanol. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 16 hours in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.17 dL / g in HFIP at 25 ° C. This copolymer was a viscous liquid at room temperature.
[0038]
Example 9
Liquid polymers of ε-caprolactone / trimethylene carbonate in an initial molar composition of 50/50
Flame-dried 250 mL single-necked round bottom flask, 57.1 g (0.50 mol) of ε-caprolactone, 51.0 g (0.50 mol) of trimethylene carbonate, 4.4 mL of propylene glycol (USP) (60 mmol) and 0.10 mL (34 μmol) of 0.33 M stannous caprylate solution in toluene were charged. A flame-dried mechanical stirrer was attached to the flask. The flask was purged with nitrogen three times before evacuating with nitrogen. The reaction mixture was heated to 160 ° C. and maintained at this temperature for about 18-20 hours. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 16 hours in order to remove any unreacted monomer. The copolymer exhibited an inherent viscosity of 0.20 dL / g in HFIP at 25 ° C. This copolymer was a viscous liquid at room temperature.
[0039]
Example 10
Liquid polymers of ε-caprolactone / trimethylene carbonate in an initial molar composition of 90/10
In a flame-dried 250 mL one-necked round bottom flask, 102.7 g (0.90 mol) of ε-caprolactone, 10.2 g (0.10 mol) of trimethylene carbonate, and 2.9 mL of propylene glycol (USP) (40 mmol) and 0.10 mL (34 μmol) of 0.33 M stannous caprylate solution in toluene was charged. A flame-dried mechanical stirrer was attached to the flask. The flask was purged with nitrogen three times before evacuating with nitrogen. The reaction mixture was heated to 160 ° C. and maintained at this temperature for about 18-20 hours. The copolymer was dried under vacuum (0.1 mm Hg) at 80 ° C. for about 16 hours in order to remove any unreacted monomer. This copolymer exhibited an inherent viscosity of 0.25 dL / g in HFIP at 25 ° C. This copolymer was a viscous liquid at room temperature.
[0040]
Example 11
Viscosity of liquid absorbent copolymers
This example provides viscosity data for liquid absorbent polymers prepared in a similar manner as described in Examples 1-9.
[0041]
The viscosity of the polymers was measured by capillary fluid measurement. Viscosity data for the liquid absorbent polymers are given in Tables 1, 2 and 3.
[0042]
[Table 1]
[0043]
[Table 2]
[0044]
[Table 3]
[0045]
Reference example 1
Poly (L-lactic acid) oligomers
Poly (L-lactic acid) oligomers were prepared in the same manner as described in Example 1 of German Patent Application DE 4,235,312 A1. For example, 100.0 grams (0.94 moles) of 85 wt% L-lactic acid solution was transferred to a clean 250 mL 3-neck round bottom flask equipped with a mechanical stirrer, distillation head and stopper. The reaction vessel was evacuated (about 25 mmHg) using an aspirator, and then heated to 150 ° C. for 5 hours using an oil bath. 22 mL (1.2 mol) of water was collected. The hot poly (L-lactic acid) oligomer (A) was poured into a wide mouth jar and cooled to room temperature under a nitrogen gas atmosphere. This oligomer (A) was a highly viscous liquid showing an inherent viscosity of 0.06 dL / g in HFIP at 25 ° C. The melt viscosity of this oligomer (A) was measured with a Rheometrics RDA II viscometer and confirmed to be 18,000 poise at 25 ° C. and indeed Newtonian.
[0046]
The above operation was repeated except that the reaction time was increased to 24 hours. 25 mL of water was collected. The resulting oligomer (B) was a crystalline solid having a melting point range of 75 ° C. to 83 ° C. when measured with a Fisher-Johns melting point measuring apparatus. The inherent viscosity of the oligomer (B) was 0.15 dL / g in HFIP at 25 ° C.
[0047]
By transferring 20.0 grams of each oligomer to a 250 mL round bottom flask equipped with an adapter and mechanical stirrer with a neck connected to a dry nitrogen gas stream and a Firestone valve through a tygon tubing. A 50:50 (weight / weight) blend of oligomer (A) and oligomer (B) was prepared. The mixture was heated to 160 ° C. for 30 minutes, transferred to a wide mouth jar and cooled to room temperature under an inert atmosphere. This blend was a clear, stiff material with an inherent viscosity of 0.08 dL / g in HFIP at 25 ° C. This blend was indeed a very viscous liquid at room temperature, as shown by the slow flow through the tube overnight. Even after standing in a jar at room temperature for 5 weeks, the majority of the blend was still transparent and only its surface layer was translucent.
[0048]
The features and aspects of the present invention are as follows.
[0049]
1. A pre-filled pharmaceutical container filled with an injectable bioabsorbable liquid copolymer,
A liquid polymer selected from the group consisting of a plurality of liquid polymers of at least two different first lactone repeating units and a plurality of liquid polymers of first lactone and second lactone repeating units, the first lactone repeating unit The units are selected from the group consisting of ε-caprolactone repeat units, trimethylene carbonate repeat units, ether lactone repeat units and combinations thereof, and the second lactone repeat unit is glycolide repeat unit, lactide repeat unit, p-dioxanone repeat unit and A liquid polymer selected from the group consisting of combinations thereof, and
A container for storing the liquid polymer, wherein the container has a cylindrical storage area and the cylindrical storage area has an outlet and a terminal, the outlet having a removable sterile seal, A container having a movable sterile seal whose distal end can be advanced into the cylindrical storage area;
Containing pre-filled pharmaceutical containers.
[0050]
2. The liquid copolymer comprises from about 65 mol% to about 35 mol% ε-caprolactone repeating units and the rest being the second lactone repeating units, from about 65 mol% to about 35 mol% ether lactone repeating units. Polymers, the remainder of which is the second lactone repeat unit, from about 65 mol% to about 35 mol% of the trimethylene carbonate repeat unit and the remainder of the polymer, wherein the second lactone repeat unit is from about 65 mol% to Polymers in which about 35 mol% is ε-caprolactone repeat units and the remainder of the polymer is trimethylene carbonate repeat units, and from about 65 mol% to about 35 mol% ether lactone repeat units, the remainder being trimethylene carbonate About 0.05 selected from the group consisting of polymers that are repeating units The prefilled pharmaceutical container of paragraph 1, which is an amorphous liquid copolymer exhibiting an inherent viscosity of dL / g to about 0.5 dL / g.
[0051]
3. The liquid copolymer is poly (ε-caprolactone-co-trimethylene carbonate), poly (lactide-co-trimethylene carbonate), poly (ε-caprolactone-co-p-dioxanone), poly (trimethylene carbonate-co-p -Dioxanone), poly (ε-caprolactone-co-lactide), poly (lactide-co-1,4-dioxepan-2-one), poly (1,4-dioxepan-2-one-co-p-dioxanone) 2. The prefilled pharmacy of item 1, selected from the group consisting of: poly (lactide-co-1,5-dioxepan-2-one) and poly (1,5-dioxepan-2-one-co-p-dioxanone) container.
[0052]
4). A pharmaceutical kit suitable for administering an injectable bioabsorbable liquid copolymer suitable for use as a soft tissue repair or augmentation material, comprising:
A liquid copolymer selected from the group consisting of a plurality of liquid polymers of at least two different first lactone repeating units and a plurality of liquid polymers of first lactone and second lactone repeating units, the first lactone repeating The units are selected from the group consisting of ε-caprolactone repeat units, trimethylene carbonate repeat units, ether lactone repeat units and combinations thereof and the second lactone repeat unit is glycolide repeat unit, lactide repeat unit, p-dioxanone repeat unit and A liquid copolymer selected from the group consisting of combinations thereof, and
A device for placing the liquid polymers, wherein the device has an outlet for the liquid polymers, an ejector for releasing the liquid polymers through the outlet, and administering the liquid polymers to a site in the body A device comprising a hollow tubular member fitted into the outlet for
A pharmaceutical kit comprising:
[0053]
5. The liquid copolymer comprises from about 65 mol% to about 35 mol% ε-caprolactone repeating units and the rest being the second lactone repeating units, from about 65 mol% to about 35 mol% ether lactone repeating units. Polymers, the remainder of which is the second lactone repeating unit, about 65 mol% to about 35 mol% of the trimethylene carbonate repeating unit and the remainder of the second lactone repeating unit, about 65 mol% to Polymers in which about 35 mol% is ε-caprolactone repeat units and the remainder of the polymer is trimethylene carbonate repeat units, and from about 65 mol% to about 35 mol% ether lactone repeat units, the remainder being trimethylene carbonate Item 4. selected from the group consisting of polymers that are repeating units Pharmacy kit.
[0054]
6). The liquid copolymer is poly (ε-caprolactone-co-trimethylene carbonate), poly (lactide-co-trimethylene carbonate), poly (ε-caprolactone-co-p-dioxanone), poly (trimethylene carbonate-co-p -Dioxanone), poly (ε-caprolactone-co-lactide), poly (lactide-co-1,4-dioxepan-2-one), poly (1,4-dioxepan-2-one-co-p-dioxanone) A pharmaceutical kit according to paragraph 4, selected from the group consisting of: poly (lactide-co-1,5-dioxepan-2-one) and poly (1,5-dioxepan-2-one-co-p-dioxanone).
[0055]
7). A method of repairing or augmenting soft tissue in an animal, comprising:
Select the soft tissue of the animal to be repaired or augmented,
A soft tissue composed of a liquid polymer selected from the group consisting of a plurality of liquid polymers composed of at least two different first lactone repeating units and a liquid polymer composed of a plurality of first lactone and second lactone repeating units. An injectable bioabsorbable liquid copolymer suitable for use as a repair or augmentation material, wherein the first lactone repeat unit comprises ε-caprolactone repeat units, trimethylene carbonate repeat units, ether lactone repeat units and combinations thereof An injectable bioabsorbable liquid copolymer selected from the group and selected from the group consisting of glycolide repeat units, lactide repeat units, p-dioxanone repeat units and combinations thereof in the soft tissue of the animal. Enter That,
A method comprising stages.
[0056]
8). The liquid copolymer is a polymer in which about 65 mol% to about 35 mol% is an ε-caprolactone repeating unit and the remainder is a repeating unit of the second lactone group, and about 65 mol% to about 35 mol% is an ether lactone repeating unit. Polymers whose units are the recurring units of the second lactone group, from about 65 mol% to about 35 mol% of the trimethylene carbonate recurring units and the rest of which are the recurring units of the second lactone group, From about 65 mol% to about 35 mol% of ε-caprolactone repeat units and the remainder of the polymer is trimethylene carbonate repeat units, and from about 65 mol% to about 35 mol% of ether lactone repeat units the remainder Is selected from the group consisting of polymers wherein trimethylene carbonate repeat units The method of paragraph 7.
[0057]
9. The liquid polymer is poly (ε-caprolactone-co-trimethylene carbonate), poly (lactide-co-trimethylene carbonate), poly (ε-caprolactone-co-p-dioxanone), poly (trimethylene carbonate-co-p -Dioxanone), poly (ε-caprolactone-co-lactide), poly (lactide-co-1,4-dioxepan-2-one), poly (1,4-dioxepan-2-one-co-p-dioxanone) 9. The method of claim 8, selected from the group consisting of: poly (lactide-co-1,5-dioxepan-2-one) and poly (1,5-dioxepan-2-one-co-p-dioxanone).
[0058]
10. 9. The method of item 8, wherein the soft tissue of the animal selected is skin.
[0059]
11. 9. The method of claim 8, wherein the liquid polymer is injected into the facial soft tissue to provide facial contours.
[0060]
12 9. The method of item 8, wherein the soft tissue of the animal selected is a sphincter.
[0061]
13. 9. The method of item 8, wherein the soft tissue of the animal selected is urinary bladder.
Claims (2)
該液状ポリマーを貯蔵するための容器であって、該容器が筒状貯蔵領域と該筒状貯蔵領域の出口および末端を有し、出口が取り外し可能無菌シールを有し、末端が該筒状貯蔵領域の中に進み得る可動性無菌シールを有する容器、を含んでなる、注射可能な生吸収性液状コポリマーが中に充填されている前充填薬学容器。Per 1 dL of a solution of hexafluoroisopropanol at 25 ° C. selected from the group consisting of a plurality of liquid polymers of at least two different first lactone repeat units and a plurality of liquid polymers of first lactone and second lactone repeat units A liquid polymer having an inherent viscosity of 0.5 dL / g or less measured at 0.10 g, wherein the first lactone repeating unit is ε-caprolactone repeating unit, trimethylene carbonate repeating unit, ether lactone repeating unit, and combinations thereof A liquid polymer selected from the group consisting of, and wherein the second lactone repeat unit is selected from the group consisting of glycolide repeat units, lactide repeat units, p-dioxanone repeat units, and combinations thereof, and the liquid poly A container for storing a over, the container has an outlet and ends of the tubular storage area and the cylindrical storage area, an outlet has a removable sterile seal, ends of the tubular storage area A pre-filled pharmaceutical container filled with an injectable bioabsorbable liquid copolymer comprising a container having a movable sterile seal that can be advanced therein.
該液状ポリマー類を入れるデバイスであって、該デバイスが該液状ポリマー類のための出口、出口を通して該液状ポリマー類を放出させるための排出器、および液状ポリマー類を体内の部位に投与するために出口にはめ込まれる中空管状部材を有するデバイス、を含んでなる、軟組織の修復または増補材料として用いるのに適した注射可能な生吸収性液状コポリマーを投与するのに適した薬学キット。Per 1 dL of a solution of hexafluoroisopropanol at 25 ° C. selected from the group consisting of a plurality of liquid polymers of at least two different first lactone repeat units and a plurality of liquid polymers of first lactone and second lactone repeat units A liquid copolymer having an inherent viscosity of 0.5 dL / g or less measured at 0.10 g, wherein the first lactone repeating unit is ε-caprolactone repeating unit, trimethylene carbonate repeating unit, ether lactone repeating unit and combinations thereof A liquid copolymer selected from the group consisting of, and wherein the second lactone repeat unit is selected from the group consisting of glycolide repeat units, lactide repeat units, p-dioxanone repeat units, and combinations thereof, and the liquid A device containing limers, the device having an outlet for the liquid polymers, an ejector for releasing the liquid polymers through the outlet, and an outlet for administering the liquid polymers to a site in the body A pharmaceutical kit suitable for administering an injectable bioabsorbable liquid copolymer suitable for use as a soft tissue repair or augmentation material comprising a device having a hollow tubular member fitted therein.
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US32495294A | 1994-10-18 | 1994-10-18 | |
US324952 | 1994-10-18 |
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JP29382895A Expired - Fee Related JP3685217B2 (en) | 1994-10-18 | 1995-10-18 | Injectable liquid copolymers for soft tissue repair and augmentation |
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EP (1) | EP0711794B1 (en) |
JP (1) | JP3685217B2 (en) |
AU (1) | AU706434B2 (en) |
BR (1) | BR9504448A (en) |
CA (1) | CA2160853C (en) |
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JP3257750B2 (en) * | 1993-07-20 | 2002-02-18 | エチコン・インコーポレーテツド | Liquid copolymer of ε-caprolactone and lactide |
-
1995
- 1995-10-12 AU AU34222/95A patent/AU706434B2/en not_active Ceased
- 1995-10-17 EP EP95307369A patent/EP0711794B1/en not_active Expired - Lifetime
- 1995-10-17 DE DE69519912T patent/DE69519912T2/en not_active Expired - Lifetime
- 1995-10-17 ZA ZA958768A patent/ZA958768B/en unknown
- 1995-10-18 JP JP29382895A patent/JP3685217B2/en not_active Expired - Fee Related
- 1995-10-18 CA CA002160853A patent/CA2160853C/en not_active Expired - Fee Related
- 1995-10-18 BR BR9504448A patent/BR9504448A/en not_active IP Right Cessation
-
1996
- 1996-11-06 US US08/746,180 patent/US5824333A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH08224298A (en) | 1996-09-03 |
AU706434B2 (en) | 1999-06-17 |
BR9504448A (en) | 1997-05-20 |
EP0711794A1 (en) | 1996-05-15 |
EP0711794B1 (en) | 2001-01-17 |
DE69519912D1 (en) | 2001-02-22 |
CA2160853C (en) | 2007-04-03 |
ZA958768B (en) | 1997-04-17 |
US5824333A (en) | 1998-10-20 |
AU3422295A (en) | 1996-05-02 |
CA2160853A1 (en) | 1996-04-19 |
DE69519912T2 (en) | 2001-06-13 |
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